20-bit esterified camptothecine derivate, its preparation method and drug composite and use

A compound and low-level technology, which can be used in drug combinations, medical preparations containing active ingredients, organic chemistry, etc., and can solve the problems of high toxicity and low anti-tumor activity.

Inactive Publication Date: 2007-05-02
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since camptothecin and 10-hydroxycamptothecin are unmodified natural products, they are highly toxic and have low anti-tumor activity, which limits their clinical app

Method used

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  • 20-bit esterified camptothecine derivate, its preparation method and drug composite and use
  • 20-bit esterified camptothecine derivate, its preparation method and drug composite and use
  • 20-bit esterified camptothecine derivate, its preparation method and drug composite and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Camptothecin-20-O-2-(pyridine-4-)thioacetic acid ester

[0111] Add 30 mg (0.0861 mmol) camptothecin, 30 mg (0.172 mmol) 2-(pyridine-4-) thioglycolic acid, 66 mg (0.344 mmol) 1-[(3- Dimethylamino)propyl]-3-ethylcarboximide hydrochloride (EDCI), 10 mg (0.0819 mmol) 4-dimethylaminopyridine (DMAP) and 5 mL of anhydrous dichloromethane, and the reaction mixture was stirred at room temperature After 10 hours, the reaction solution was diluted with 50 mL of chloroform, then successively washed with 50 mL of water, 50 mL of saturated NaHCO 3 solution and 50mL saturated brine, adding anhydrous MgSO 4 Dry, filter to remove MgSO 4 Finally, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: chloroform-methanol 100:1) to obtain 26 mg of white solid, yield: 60%, mp: 207-210°C, 1 H NMR (400MHZ, CDCl 3 ): δ8.41(s, 1H, Ar-H), 8.24(m, 3H, Ar-H), 7.97(d, J=8.0Hz, 1H, Ar-H), 7.88(t, J=7.2Hz , 1H, Ar-H), 7.7...

Embodiment 2

[0113] Camptothecin-20-O-2-(thymine-1-)acetate

[0114]

[0115] Add 40 mg (0.106 mmol) camptothecin, 60 mg (0.326 mmol) 2-(thymine-1-) acetic acid, 80 mg (0.424 mmol) 1-[(3-di Methylamino)propyl]-3-ethylcarbimide hydrochloride (EDCI), 10 mg (0.0819 mmol) 4-dimethylaminopyridine (DMAP) and 5 mL of anhydrous dichloromethane, and the reaction mixture was stirred at room temperature for 24 Hours, the reaction solution was diluted with 50mL chloroform, then successively with 50mL water, 50mL saturated NaHCO 3 solution and 50mL saturated brine, adding anhydrous MgSO 4 Dry, filter to remove MgSO 4 Finally, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: chloroform-methanol 100:1) to obtain 14 mg of a yellow solid, yield: 24%, mp: 206-208°C, 1 H NMR (400MH Z , CDCl 3 ): δ8.50(s, 1H, Ar-H), 8.44(d, J=8.0Hz, 1H, Ar-H), 8.00(d, J=8.0Hz, 1H, Ar-H), 7.91(t , J=7.6Hz, 1H, Ar-H), 7.74(t, J=7.6Hz, 1H, A...

Embodiment 3

[0117] Camptothecin-20-O-2-[(4-methylpyrimidine)-2-]thioglycolate

[0118]

[0119] Add 40mg (0.115mmol) camptothecin, 52mg (0.282mmol) 2-[(4-methylpyrimidine)-2-]thioglycolic acid, 90mg (0.469mmol) 1-[(3-Dimethylamino)propyl]-3-ethylcarboximide hydrochloride (EDCI), 10 mg (0.0819 mmol) 4-dimethylaminopyridine (DMAP), and 5 mL of anhydrous dichloromethane , the reaction mixture was stirred at room temperature for 12 hours, the reaction solution was diluted with 50 mL of chloroform, then successively washed with 50 mL of water, 50 mL of saturated NaHCO 3 solution and 50mL saturated brine, adding anhydrous MgSO 4 Dry, filter to remove MgSO 4 Finally, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: chloroform-methanol 100:1) to obtain 50 mg of a yellow solid, yield: 85%, mp: 231-233°C, 1 H NMR (400MH Z , CDCl 3 ): δ8.40(s, 1H, Ar-H), 8.21(d, J=8.0Hz, 1H, Ar-H), 7.97(d, J=8.0Hz, 1H, Ar-H), 7.8...

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Abstract

This invention discloses a new camptothecin derivate of 20-position esterification, its preparation, containing their medicine combination, and its usage of using it as medicine, especially as antitumor drug.

Description

technical field [0001] The present invention relates to novel 20-esterified camptothecin derivatives, their preparation method, their pharmaceutical composition, and their use as medicine, especially as antitumor medicine. Background technique [0002] Camptothecin (CPT) is an alkaloid isolated from Camptotheca acuminata. Experiments have proved that camptothecin has anticancer activity on many solid tumors. It mainly acts on DNA topoisomerase I (Topo I, an enzyme highly expressed in many cancer cells), and is the most classic specific inhibitor of Topo I. agent. Topo I is currently one of the most popular targets for designing new anticancer drugs. The National Cancer Institute (NCI) drug mechanism analysis computer network system has listed Topo I inhibitors as one of the six major anti-tumor drugs for key research. In addition to the United States and Japan, France, Germany, Italy and South Korea are also conducting research on camptothecin derivatives. [0003] In vi...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61K31/496A61P35/00C07D221/00C07D209/00C07D311/00
Inventor 温显道刘红岩
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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